Synthesis of a Precursor to Sacubitril Using Enabling Technologies.

Shing-Hing Lau,Gerhard Penn,Berthold Schenkel,Benjamin Martin,Steven V Ley,Samuel L Bourne

doi:10.1021/acs.orglett.5b02806

Shing-Hing Lau, Gerhard Penn + Show 4 more

Open Access

https://doi.org/10.1021/acs.orglett.5b02806

Copy DOI

Abstract

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Highlights

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively (Figure 1).[3]
With the spotlight on LCZ696, we describe an alternative synthetic strategy for the synthesis of sacubitril precursor 3 via a machine-assisted approach
We investigated the optimum conditions for the homogeneous stereoselective hydrogenation[20] of acrylic acid 6 in flow (Scheme 6).[21]

Summary

Introduction

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively (Figure 1).[3]. The key steps involved a Wittig reaction between biphenyl amino aldehyde and (carbethoxyethylidene)triphenylphosphorane followed by a stereoselective hydrogenation of the resulting internal double bond of acrylic ester 4 (Scheme 1a).

Results

Conclusion